Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, and Department of Biochemistry and Molecular Biology, University of Florida College of Medicine, Gainesville, FL.
J Natl Cancer Inst. 2017 Nov 1;109(11). doi: 10.1093/jnci/djx071.
The mitochondrial pyruvate dehydrogenase complex (PDC) irreversibly decarboxylates pyruvate to acetyl coenzyme A, thereby linking glycolysis to the tricarboxylic acid cycle and defining a critical step in cellular bioenergetics. Inhibition of PDC activity by pyruvate dehydrogenase kinase (PDK)-mediated phosphorylation has been associated with the pathobiology of many disorders of metabolic integration, including cancer. Consequently, the PDC/PDK axis has long been a therapeutic target. The most common underlying mechanism accounting for PDC inhibition in these conditions is post-transcriptional upregulation of one or more PDK isoforms, leading to phosphorylation of the E1α subunit of PDC. Such perturbations of the PDC/PDK axis induce a "glycolytic shift," whereby affected cells favor adenosine triphosphate production by glycolysis over mitochondrial oxidative phosphorylation and cellular proliferation over cellular quiescence. Dichloroacetate is the prototypic xenobiotic inhibitor of PDK, thereby maintaining PDC in its unphosphorylated, catalytically active form. However, recent interest in the therapeutic targeting of the PDC/PDK axis for the treatment of cancer has yielded a new generation of small molecule PDK inhibitors. Ongoing investigations of the central role of PDC in cellular energy metabolism and its regulation by pharmacological effectors of PDKs promise to open multiple exciting vistas into the biochemical understanding and treatment of cancer and other diseases.
线粒体丙酮酸脱氢酶复合物（PDC）不可逆地将丙酮酸脱羧为乙酰辅酶 A，从而将糖酵解与三羧酸循环联系起来，并定义了细胞生物能量学中的一个关键步骤。PDC 活性被丙酮酸脱氢酶激酶（PDK）介导的磷酸化抑制与许多代谢整合障碍的病理生物学有关，包括癌症。因此，PDC/PDK 轴一直是一个治疗靶点。这些情况下 PDC 抑制的最常见潜在机制是一种或多种 PDK 同工型的转录后上调，导致 PDC 的 E1α 亚基磷酸化。PDC/PDK 轴的这种干扰诱导“糖酵解转移”，受影响的细胞通过糖酵解而不是线粒体氧化磷酸化以及细胞增殖而不是细胞静止来优先产生三磷酸腺苷。二氯乙酸是 PDK 的典型外源物抑制剂，从而使 PDC 保持未磷酸化的、催化活性形式。然而，最近对 PDC/PDK 轴作为癌症治疗的治疗靶点的治疗靶向的兴趣产生了新一代小分子 PDK 抑制剂。PDKs 的药理学效应物对 PDC 在细胞能量代谢中的核心作用及其调节的持续研究有望为癌症和其他疾病的生化理解和治疗开辟多个令人兴奋的前景。
